Investigations of Cell-Penetrating and Membrane-Pore Forming Peptides

Authors

Rudramani Pokhrel, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Physics

First Advisor's Name

Prem P. Chapagain

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Bernard S. Gerstman

Second Advisor's Committee Title

committee chair

Third Advisor's Name

Xuewen Wang

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

Jaroslava Miksovska

Fourth Advisor's Committee Title

committee member

Keywords

Molecular Dynamics Simulations, Virus, Bacteria, Ebola, Lantibiotics, Mutacin, Nisin, Delta Peptide

Date of Defense

10-23-2020

Abstract

Cell-penetrating and membrane-pore forming peptides are a class of membrane-active peptides. They are short sequence peptides having both hydrophilic and lipophilic combinations of amino acids. These peptides can have contrast functional diversity. Peptides encoded by viruses function as viroporins and play a critical role in viral replication, propagation, and pathogenesis. One such peptide is the Ebola virus delta peptide, which forms a pore in the host cell membrane. Another set of pore-forming peptides are antimicrobial Lantibiotic peptides that may be useful for killing antibiotic resistant bacteria by disrupting the bacterial membrane through two different possible mechanisms. Not only can they form pores that disrupt the bacterial membrane, Lantibiotics can also hinder the function of a bacterial membrane molecule, Lipid II, that is essential for cell wall biosynthesis.

I performed Molecular Dynamics (MD) simulation to investigate the membrane pore-forming mechanism of the Ebola virus delta peptide. I found that the Ebola virus delta peptide forms a pentameric pore in the host cell membrane. The pore is selective for negatively charged ions, and the disulfide link between Cysteine 29 and 38 is essential for stable and effective membrane-pore formation. Similarly, I studied Lipid II binding and membrane-pore forming activity of several Lantibiotics: Nisin, Mutacin 1140, Gallidermin, NAI107, and NVB302. The computational results from MD simulations show that Nisin forms the most effective water channel in the bacterial membrane, but Gallidermin has the best Lipid II binding profile. Mutacin 1140 also binds strongly with Lipid II and forms an efficient water channel in the bacterial membrane. I also performed MD computations on a variety of mutated peptides of Mutacin 1140 and the Ebola virus delta peptides and investigated their water solubility, Lipid II binding, and membrane insertion profile. These results provide insight into the possible antimicrobial peptides with an optimized drug profile.

Identifier

FIDC009195

ORCID

https://orcid.org/0000-0002-7208-0420

Previously Published In

1. R. Pokhrel, E. Pavadai, B.S. Gerstman, P.P. Chapagain, Membrane pore formation and ion selectivity of the Ebola virus delta peptide, Phys Chem Chem Phys, 21 (2019) 5578-5585.

2. R. Pokhrel, N. Bhattarai, P. Baral, B.S. Gerstman, J.H. Park, M. Handfield, P.P. Chapagain, Molecular mechanisms of pore formation and membrane disruption by the antimicrobial lantibiotic peptide Mutacin 1140, Phys Chem Chem Phys, 21 (2019) 12530-12539.

Recommended Citation

Pokhrel, Rudramani, "Investigations of Cell-Penetrating and Membrane-Pore Forming Peptides" (2020). FIU Electronic Theses and Dissertations. 4592.
https://digitalcommons.fiu.edu/etd/4592